Abstract
In the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages. In this process, the ESCRT proteins, ALIX and TSG101, are recruited through interactions with HIV-1 Gag p6. ALG-2, also known as PDCD6, interacts with both ALIX and TSG101 and bridges ESCRT-III and ESCRT-I. In this study, we show that ALG-2 affects HIV-1 production negatively at both the exogenous and endogenous levels. Through a yeast two-hybrid screen, we identified HEBP2 as the binding partner of ALG-2, and we solved the crystal structure of the ALG-2·HEBP2 complex. The function of ALG-2·HEBP2 complex in HIV-1 replication was further explored. ALG-2 inhibits HIV-1 production by affecting Gag expression and distribution, and HEBP2 might aid this process by tethering ALG-2 in the cytoplasm.
Highlights
In the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages
ALG-2 Is a Cellular Inhibitor of HIV-1 Production—ALG-2 is known to interact with the ESCRT components ALIX and TSG101, and ESCRT is involved in HIV-1 production; we speculated that ALG-2 might affect HIV-1 production
A previous report showed that ALG-2 has no dramatic effect on HIV-1 replication in either HeLa or 293T cells using a pseudovirus system [30]; no function of ALG-2 in HIV-1 tropic cells has been tested
Summary
In the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages In this process, the ESCRT proteins, ALIX and TSG101, are recruited through interactions with HIV-1 Gag p6. The endosomal sorting complex required for transport (ESCRT) machinery functions in HIV-1 budding and release in the late stages of viral replication [1,2,3] In this process, ALIX (ALG-2 interacting protein X) and TSG101 (tumor susceptibility gene 101), components of ESCRT-III and ESCRT-I, are recruited to the budding site of HIV-1 through interactions with HIV-1 Gag p6 (4 – 8). This is the first report to establish a direct link between ALG-21⁄7HEBP2 complex and HIV-1 production
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